1. The Diabetic Retinopathy Clinical Research Network
Treatment for Central-involved DME in Eyes with Very Good Visual Acuity (DRCR.net Protocol V)

2. DRCR.net Overview Objective:
Collaborative network to facilitate multicenter clinical research of diabetic retinopathy, DME and associated conditions
Funding:
National Eye Institute (NEI) and The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored cooperative agreement initiated September 2002.
Current award

3. DRCR.net Status (as of 1/6/14)
Active
Total
Sites
(Community & Academic Centers)
119
179
Community Sites
80 (67%)
120 (67%)
Investigators
363
786
Other Personnel
979
2746
States 37 41

4. Current Clinical Question
What is the best treatment strategy for eyes with central-involved (CI) DME and good visual acuity?
Possible treatment approaches in clinical practice include:
Initiating intravitreal anti-VEGF promptly
Initiating focal/grid laser promptly
If VA worsens, begin anti-VEGF
Observing
If DME worsening on OCT, begin anti-VEGF or laser

5. What do we already know?
In the DRCR.net LRT for DME Study (Protocol I), ranibizumab + deferred or prompt laser for CI-DME provided VA outcomes superior to prompt focal/grid laser alone
However…
Only eyes with VA letter score ≤78 (20/32 or worse) were enrolled
Anti-VEGF has not been evaluated in eyes that have CI-DME with VA 20/25 or better

6. What do we already know?
In the ETDRS – eyes with CI-DME that started with 20/25 or better vision and lost 5 or more letters at 2 years:
Focal laser  27%
Observation  40%
However….
OCT not available to closely follow improvement or worsening of DME
Clinical characteristics of the cohort may have changed since the time of the ETDRS
Deferred Anti-VEGF as a rescue treatment not evaluated as part of treatment approach

7. Available 2 Year Data Summary
ETDRS
Focal
Observation
Protocol I Ranibizumab + Deferred Laser
Eyes with VA ≥20/25 or better at baseline
VA = 20/32 at baseline
N = 118
N = 246
N = 28
Visual Acuity Decrease by Letter Score of 5 or More
27%
40% 4%
Visual Acuity Decrease by Letter Score of 10 or More
13%
25%
VA Change from Baseline
Median (25th , 75th)
-1 (-5, 2)
-3 (-10, 1)
5 (1, 9)

8. ETDRS and Protocol I Data*: Percent with VA loss ≥ 5 letters
*ETDRS study eyes with CI-DME and VA 20/25 or better at baseline. Protocol I study eyes with CI-DME and VA = 20/32 at baseline

9. Study Questions
In eyes with good VA, is deferring anti-VEGF similar, better, or worse than prompt anti-VEGF for long-term visual acuity outcomes?
If similar or better, how long can you defer anti-VEGF?
What % never need anti-VEGF?
If deferring anti-VEGF, is it better to observe or give focal/grid laser?
Does one provide better VA outcomes?
Does one allow for fewer anti-VEGF injections?

10. Study Questions
If prompt anti-VEGF is better, does it have enough of a benefit to warrant risks of repeated intravitreal injections?
How many injections are needed to maintain 20/20 vision?
Are fewer injections needed in the long run than if you wait until after VA or OCT decline to initiate anti-VEGF?

11. Study Design Randomized, multi-center clinical trial (N=702)
At least one eye meeting all of the following criteria:
Central-involved DME on OCT (Cirrus/Spectralis only)*
VA letter score 20/25 or better*
No or minimal** prior treatment for DME
Prompt
anti-VEGF
Prompt laser + deferred anti-VEGF
Observation + deferred anti-VEGF
Primary outcome: Proportion of eyes that have lost ≥5 letters of VA at 2 years
*Confirmed at 2 visits (screening and randomization 1-28 days apart)
**No more than 1 laser and/or 4 injections, at least 12 months ago

12. Treatment Groups: Prompt Anti-VEGF
Treatment Group Description:
Intravitreal anti-VEGF (2.0 mg aflibercept) at randomization
DRCR.net retreatment criteria during follow-up
Rationale:
Protocol I and other studies have demonstrated that anti-VEGF is well-tolerated and more effective than laser alone in increasing vision gain and decreasing vision loss in patients with CI DME, but this benefit has not been established in eyes that have good vision despite the presence of CI DME \ 12

13. Treatment Groups: Prompt Laser + Deferred Anti-VEGF
Treatment Group Description:
Focal/grid laser at randomization
Anti-VEGF only initiated if protocol criteria met
Rationale:
The initial use of focal/grid laser could offer advantages over starting treatment with anti-VEGF in terms of reducing adverse events associated with intravitreal injections as well as fewer treatments given over time with potentially less frequent follow-up 13

14. Treatment Groups: Observation + Deferred Anti-VEGF
Treatment Group Description:
Observation
Anti-VEGF only initiated if protocol criteria met (to be discussed)
Rationale:
Deferral of immediate treatment might result in decreased inconvenience, adverse events and costs associated with anti-VEGF treatments that are performed as often as once a month while potentially preserving vision in eyes with CI DME with good vision 14

15. Major Eligibility Criteria
Type 1 or 2 diabetes
Study Eye:
Central-involved DME on clinical exam, confirmed on OCT at two consecutive visits (1-28 days apart)
VA letter score >79 (~20/25 or better) at two consecutive visits (1-28 days apart)
No or minimal history of prior DME treatment
No more than 1 laser, 4 injections at least 12 months ago
Non-study eye:
Patient must be willing to use (or switch to using) study aflibercept on the non-study eye if needed 15

16. Major Exclusion Criteria
Systemic
History of chronic renal failure requiring dialysis or kidney transplant
Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months
BP > 180/110
Study eye
Macular edema not due to DME (eyes with thickening due to ERM, prior cataract surgery or other non-DME reason should not be enrolled)
PRP in last 4 months or anticipated in next 6 months
History of intravitreal anti-VEGF for an ocular condition other than DME in last 6 months or anticipated need in next 6 months

17. Study Follow-Up Treatment Visit Schedule Outcome Visit Schedule
Prompt anti-VEGF Group: visits every 4 weeks during the first 24 weeks, every 4-16 weeks thereafter
Deferred anti-VEGF groups (focal and observation)*: visits at 8 and 16 weeks, followed by every 16-week visits thereafter
All participants will have visits at 1 and 2 years for outcome assessment
*For the deferred groups, if vision and/or OCT are worsening or anti-VEGF is initiated, visits will be every 4, 8 or 16 weeks depending on disease progression and treatment

18. Study Treatment Prompt Anti-VEGF Injection at baseline
Evaluation at each visit for re-injection based on protocol criteria
Focal/grid laser at baseline
Evaluation at each visit for initiating anti-VEGF based on visual acuity loss
Retreatment with laser if protocol criteria are met
Laser +
Deferred
Anti-VEGF
Observe +
Deferred
Anti-VEGF
No treatment at baseline
Evaluation at each visit for initiating anti-VEGF based on visual acuity loss

19. Referrals We Need Your Help!
Please consider any eyes with DME involving the center of the macula and vision ~20/32 or better on clinic charts
Study participants must be willing to be randomized to laser, injections, or observation to start and continue follow-up for 2 years
Consenting/Screening/Randomization will be split into several visits
An optional “Observational Phase” is also available for patients not ready for randomized treatment

20. Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
Dedicated to multicenter clinical research of diabetic retinopathy, macular edema and associated disorders. 20